According to article 10.4 of the Terrestrial Animal Health Code, highly pathogenic influenza A viruses are those isolates (strains) thereof for which an intravenous pathogenicity index is greater than 1.2 [Terrestrial Animal Health Code, 2008 http://www.oie.int/eng/hormes/mcode/en_chapitre_1.10.4.html].
Another criterion for classifying isolates of influenza A virus strains (for example, H5N1) as highly pathogenic is the dose of this pathogen killing 50% of intranasally infected white mice. Highly pathogenic influenza A virus strains in mice are those having LD50 of less than 5.5 lg EID50 [Maines, T. R., Lu, X. H., Erb, S. M., et al., “Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals,”//J. Virol, 2005, Vol. 79, No. 18, pp. 11788-11800].
The major tools for the prevention and control of epidemic (pandemic) influenza are chemotherapy, chemoprophylaxis, and vaccination.
In view of the impossibility of predicting the antigenic structure of a future epidemic (pandemic) influenza A virus, the early design of effective influenza vaccines is difficult, and it is therefore important to have in the arsenal chemotherapeutic agents for the prophylaxis and treatment of diseases caused by highly pathogenic virus strains.
Arbidol® is one of the most common medications for the treatment and prophylaxis of viral infections, specifically influenza. In oral administration in vivo tests for emergency prevention and treatment (135 mg/kg body weight in white mice), however, the protective efficacy of Arbidol® against the highly pathogenic influenza A (H5N1) virus strain is as low as 25 and 10%, respectively (see Tables 2 and 3).
This protection level does not meet the existing national requirements for the efficacy of antiviral chemotherapeutics (which should be no less than 30%) [       —M., 2005.—C. 541 (The Manual on Experimental (Preclinical) Study of Novel Pharmacological Agents, Moscow, 2005, p. 541)].
Adamantane derivatives are also well-known chemotherapeutics, which have been in use in the therapy of seasonal influenza since the 1960s. The recently isolated strains of highly pathogenic influenza A(H5N1) virus had a high-level resistance to adamantane derivatives, namely to amantadine and rimantadine; for this reason, these medications have lost their therapeutic role [Cheung, C. L., Rayner, J. M., Smith, G. J., et al., “Distribution of Amantadine-Resistant H5N1 Avian Influenza Variants in Asia,” J. Infect. Dis., 2006, Vol. 193, pp. 1626-1629].
Neuraminidase inhibitor oseltamivir is the most efficient agent for treating influenza. Many influenza A subtype H5N1 virus strains have recently acquired resistance to oseltamivir due to the replacement of one amino acid in neuraminidase N1 (His274Tyr and N294S) [Hui-Ling, Y., Ilyshina, N. A., Salomon, R., et al. “Neuraminidase Inhibitor-Resistant Recombinant A/Vietnam/1203/04 (H5N1) Influenza Viruses Retain Their Replication Efficacy and Pathogenicity in vitro and vivo,” J. Virol, 2007, Vol. 81, pp. 12418-12426; Le, Q. M., Kiso, M., Someya, K., et al. “Avian Flu: Isolation of Drug-Resistant H5N1 Virus,” Nature, 2005, Vol. 437, p. 1108].
Thus, the medications commonly used against seasonal influenza strains prove to be inefficient against highly pathogenic strains.
One more highly pathogenic viral disease is severe acute respiratory syndrome (SARS), a new acute coronavirus disease which is caused by the genotype IV pathogen and characterized by up to 10% mortality [Revised U.S. Surveillance Case Definition for Severe Acute Respiratory Syndrome (SARS) and Update on SARS Cases, United States and Worldwide, December 2003, MMWR Wkly Rep., 2003, Vol. 52, No. 49, pp. 1202-1206].
Therefore, there is a need in developing new agents for the treatment and/or prophylaxis of highly pathogenic influenza and SARS. The inventors unexpectedly found that glutaryl histamine is useful as such an agent and this resulted in the development of the present invention.